Each mammalian cell carries two copies of each gene, one inherited from the mother (on the maternal chromosome) and one inherited from the father (on the paternal chromosome). Most of the autosomal genes and X-linked genes in females are therefore biallelic i.e. both paternal and maternal alleles of the gene are expressed and the information of both copies is actively used in protein synthesis. In males, sex-linked genes are generally monoallelic since there is one X and one Y chromosome. Only a few genes on the Y chromosome have functional homologs on the X chromosome and are biallelic.
However, in humans and other mammals, monoallelic expression of biallelic genes has been demonstrated. These include genes on the inactive X-chromosome, genes encoding IL-2, IL-4, PAX-5, subunits of olfactory and lymphocyte receptors and imprinted genes. Allelic exclusion can result from two different mechanisms. The first mechanism is independent of the parental origin. One allele is randomly repressed and the pattern of allelic exclusion is transmitted stably to the daughter cells. This allelic exclusion can be due to X-chromosome inactivation, to programmed DNA rearrangement (B and T cell receptor in lymphocytes) or to other unknown mechanisms. The second mechanism, called genomic imprinting, is the result of a mark or imprint carried by a region of the chromosome and that reflects the parental origin. Imprinted genes in the mammalian genome are the genes for which one of the parental alleles is repressed whereas the other one is transcribed and expressed. Many imprinted genes are located in clusters and are associated with CpG-rich regions called CpG islands that are methylated uniquely on a specific parental chromosome (Razin A. and Cedar H. (1994) Cell, 77:473–476; Constancia M et al. (1998) 8:881–900, Reik W. and Walter J. (2001) Nature Rev. Genet., 2:21–32 incorporated in their entity by reference for all purposes).
About sixty imprinted genes have been discovered in the mouse. An estimate of one to two hundred imprinted genes has been proposed based on mouse models (Barlow D. P. (1995) Science, 270: 1610–1613; Morison I. M. et al. (2001), Nucl. Acids Res., 29:275–276 each of which is incorporated herein by reference in its entirety; databases available at http://www.otago.ac.nz/IGC and http://www.geneimprint.com).
Imprinted genes tend to occur in clusters in both the human and mouse genomes (Reik W. and Walter J. (1998) Curr. Opin. Genet., 8:154–164), which is incorporated herein by reference in its entirety. For example, in humans, two chromosomal regions (11p15.5 and 15q11–q13) harbor more than one imprinted gene. Some imprinted genes, such as Igf2 (Insulin-like growth factor type 2) and H19 (a non-coding RNA involved in silencing Igf2 expression) are located in imprinted clusters of genes that show coordinate regulation.
Imprinted genes can show monoallelic expression in some tissues and biallelic expression in others. For example, Igf2 is imprinted in most tissues but is biallelic in brain, liver and several other tissues. Monoallelic expression or disruption of monoallelic expression of some genes can lead to a disease phenotype. For instance, imprinting is a factor in an increasing number of genetic diseases such as Prader-Willi syndrome, Angelman syndrome, and Beckwith-Wiedmann syndrome. Imprinted genes and imprinting mechanisms are therefore important in human birth defects, cancer and in some neurological and psychiatric disorders (for review, see Falls G. J. et al. (1999) Am. J. Path., 154:635–647).
Monoallelic expression of some genes that are present in two copies is required for normal development and viability. For example, human females have two copies of the X chromosome while males have a single X chromosome. However, females have effectively only a single copy of the X chromosome due to inactivation of one copy of the X chromosome in each cell. The inactive copy is known as a Barr body and inactivation is required for normal development. Inactivation of the X chromosome is random, resulting in mosaicism, meaning that in some cells the paternal copy of the X chromosome is inactivated and in some cells the maternal copy is inactivated. For genes that are present in a different allelic form on the paternal and maternal X chromosomes this results in expression of one allele in some cells and the other allele in other cells.